Acylated enamides and pharmaceutical compositions containing them

ABSTRACT

The acylated enamide compounds are acylated enamides corresponding to the general formula ##STR1## in which Z represents an electron donor group, 
     n is 1, 2 or 3, and 
     R 1  represents hydrogen, a halogen or any organic group, 
     or salts, complexes, alkylated derivatives or acylated derivatives of these compounds. 
     Typical acylated enamide compounds according to the invention correspond to the formula ##STR2## These acylated enamide compounds and the pharmaceutical compositions containing the compounds are useful in the prevention and treatment of cancers.

The present invention relates to acylated enamide compounds consistingof acylated enamides as well as their salts, their complexes and theiracylated and alkylated derivatives. The invention also relates topharmaceutical compositions which contain these compounds and which canin particular be used for the prevention or treatment of cancers, theuse of these compounds for the prevention of cancers and a process forthe preparation of these compounds.

The acylated enamide compounds according to the invention are compoundscorresponding to the general formula: ##STR3## in which Z represents anelectron donor group,

n is 1, 2 or 3, and

R¹ represents hydrogen, a halogen or any organic group,

or salts, complexes, alkylated derivatives of acylated derivatives ofthese compounds.

The salts of these compounds can for example be ammonium salts, alkalimetal salts such as the sodium or potassium salt, alkaline earth metalsalts such as the magnesium and calcium salts, and salts of organicbases. The complexes of these compounds can be those formed with, forexample, any metal salts. By acylated derivatives of these compounds,there are understood derivatives such as the esters and the amides ofthese compounds; preferably, the aromatic nucleus carrying the group Zdoes not contain acylated substituents.

Usually, the donor group is a halogen or a group selected from amongstthe groups OR², SR², SeR², N═R² or NR² R³, in which the oxygen, sulphur,selenium and nitrogen can form part of a ring and R² and R³ can beidentical or different and represent hydrogen or a saturated orunsaturated aliphatic or cyclic organic group containing from 1 to 20carbon atoms. Most commonly, R² and R³ represent a substituted orunsubstituted alkyl group containing from 1 to 6 carbon atoms.Preferably, the donor group is an OR² group, where R² representshydrogen or a substituted or unsubstituted alkyl group containing from 1to 6 carbon atoms. A very particularly preferred donor group is amethoxy group --OCH₃.

Usually, R¹ represents hydrogen, a halogen or any organic group.Preferably, R¹ represents hydrogen or a substituted or unsubstitutedaliphatic group containing from 1 to 4 carbon atoms, or an aromaticgroup containing from 5 to 8 carbon atoms. A particularly preferredmeaning of R¹ is hydrogen.

The preferred acylated enamide compounds according to the invention arethe (methoxyphenylacetyl)dehydroalanines of the formula ##STR4## Amongstthese, the preferred acylated enamide compound is that in which themethoxy substituent is in the paraposition.

A process for the preparation of acylated enamide compounds according tothe invention consists of reacting an amide of the formula ##STR5##where R¹, Z and n are as defined above, with pyruvic acid. The reactioncan be carried out by bringing 1 mol of amide together with 1.2 mols offreshly distilled pyruvic acid and heating these, in benzene, to thereflux temperature in an apparatus equipped with a water separator.Refluxing is stopped when water ceases to separate out. The mixture isleft until a precipitate forms and is then filtered, and the precipitateis treated with a saturated NaHCO₃ solution. The fraction which isinsoluble in a basic medium and which consists of unreacted amide isseparated off and concentrated hydrochloric acid is then added graduallyto the filtrate until a pH of about 3.5 and a precipitate result. Afterfiltration and recrystallisation from ethanol, yields of between 30% and95% are obtained. It can happen that a precipitate is not obtained afterrefluxing in benzene solution; in that case, the benzene is evaporatedand the residue is treated in the same manner as described above.

The acylated enamide compounds according to the invention can also beprepared by any other appropriate organic synthesis. For example, theprocess described in French Pat. No. B-2,349,567 (SUMITOMO CHEMICALCOMPANY) can be employed.

The acylated enamide compounds according to the invention can be used asmedicaments and especially for the treatment, in human or veterinarymedicine, of all malignant tumoral proliferations such as cancers ofvarious origins, regardless of the age and histological type of thetissue at the expense of which these cancers have formed. The compoundscan also be used for the prevention of these same diseases, for exampleby using the compounds as a food additive.

The invention also relates to the parmaceutical compositions containingas the active ingredient an acylated enamide compound as defined above.These compounds can furthermore contain an antineoplastic substance forsimultaneous, separate or long-term use in cytostatic therapy. The knownantineoplastic substances generally suffer from the serous disadvantageof having a high degree of toxicity which causes particularly harmfulsecondary effects such as damage to the normal tissues. Thepharmaceutical compositions according to the invention have both areduced degree of toxicity and an improved therapeutic effect comparedto the known compositions containing only antineoplastic substances.

By an antineoplastic substance there is meant any substance which can beused for the purpose of destroying the cancer cells or preventing theirappearance and proliferation. Compounds of very diverse chemical natureare known to be antineoplastic substances; they include alkylatingagents such as cyclophosphamide, melphalan, chlorambucil, chlormetineand other nitrogen mustards, ethyleneimines, an example being thiothepa,sulphonic esters including busulfan, antimetabolites such asmethotrexate and other anti-folic acid compounds, mercaptopurine andother anti-purine compounds, fluorouracil, cytarabine and otheranti-pyrimidine compounds, azaserine, hormonal modifiers such as theandrogens, the oestrogens, the progestational agents and theglucocorticoids, enzymes such as asparaginase, antibiotics such asbleomycin, dactinomycin, daunorubicin, meractinomycin, mitomycin,rufocromycin, methramycin, doxorubicin (sometimes called adriamycin),plant extracts such as alkaloids from the periwinkle and the colchicumand other fusorial poisons, radioactive isotopes such as sodiumradiophosphate, sodium radioiodide or other compounds such asmethylglyoxal bis(guanylhydrazone), derivatives of podophyllotoxin,mitotane, pipobromane, nitrosoureas and hydroxyurea. The antineoplasticsubstances preferably present in the pharmaceutical compositionsaccording to the invention are the nitrogen mustards, the antibioticsand anti-pyrimidine compounds and very especially cyclophosphamide,daunorubicin, doxorubicin and fluorouracil.

The pharmaceutical compositions according to the invention can be usedfor the treatment and prevention in human medicine or veterinarymedicine, of all malignant tumoral proliferations such as cancers.

The pharmaceutical compositions according to the invention can alsocontain other active substances which can be used in pharmaceuticalcompositions for the prevention or treatment of cancers, and especiallyascorbic acid.

Of course they also contain formulating additives which allow thecompositions to be administered conveniently, to example in the form ofpowders, tablets, ointments, lotions, capsules, coated tablets, pills,ampoules, syrups, emulsions, suppositories, injections or solutions.These additives can be suitable solid or liquid, organic or inorganicvehicles or pharmaceutical assistants, such as water, organic solventsof the paraffin type, gelatine, lactose, starch, magnesium stearate,talc, vegetable and animal fats and oils, gum, polyalkylene glycols orbinders and other conventional assistants.

The pharmaceutical compositions according to the invention in generalcontain between 10% and 99% by weight of acylated enamide compoundsaccording to the invention and, optionally, an antineoplastic substance.The weight ratio of the amounts of antineoplastic substance to acylatedenamide compounds according to the invention present in the compositionsaccording to the invention is in general between 1/10 and 10/1 andpreferably between 1/4 and 4/1.

The acylated enamide compounds and the pharamceutical compositionsaccording to the invention can be administered for the treatment orprevention of malignant tumoral proliferations such as cancers in allmammals, but in particular in human patients, the administration beingin the form of one or more "dosage units", in a pharmaceuticallyeffective amount.

All methods of administration may be used, such as oral, rectal orparenteral administration as well as administration by epidermalapplication of various types of ointments or epidermal patches. Byparenteral administration there are understood intravenous andintramuscular injections, as well as perfusion.

The pharmaceutical compositions according to the invention can beadministered orally in human medicine in dosage units which in generalcontain at least 0.05 mg and up to 500 mg, preferably from 0.5 mg to 50mg, of acrylated enamide compounds according to the invention and,optionally, an antineoplastic substance, together with a non-toxicpharmaceutically acceptable vehicle. Optionally, the pharmaceuticalcompositions according to the invention and the antineoplasticsubstances can be administered separately and at different times; inthat case it is preferred to administer the pharmaceutical compositionsaccording to the invention before administering the antineoplasticsubstances, the latter being administered after from 1 hour to 24 hours.

By "dosage unit" there is understood a unit dose which can beadministered to a patient and can easily be handled and packaged so asto remain in the form of a physically stable unit dose containing theactive ingredient either alone or mixed with solid or liquidpharmaceutical diluents or vehicles.

In the form of dosage units, the pharmaceutical compositions accordingto the invention can be administered once or several times daily atappropriate intervals, but at a [1 times taking account of the conditionof the patient and the physician's prescriptions. The appropriate dailydose of the compositions according to the invention in general variesfrom 0.01 mg to 50 mg per kg of body weight.

For parenteral administration, especially for intravenous orintramuscular injections, the compositions according to the inventionare for example administered in aqueous solution or suspension, in theform of a dosa unit containing from 0.5 mg to 50 mg of acylated enamidecompound according to the invention, optionally together with anantineoplastic substance, the dosage unit being dissolved or suspendedimmediately before use or beino ready-to-use together with apharmaceutically acceptable vehicle; an example of the ready-to-use formis an injectable ampoule.

In therapy employing sustained treatment, pills or capsules can be thesuitable form of pharmaceutical preparation because of the long-lastingeffects obtained when the medicament is administered orally.

The examples which follow illustrate the invention.

EXAMPLE 1 Preparation of para-(methoxyphenylacetyl)-dehydroalanine

4.95 g (3×10⁻² mol) of para-(methoxyphenyl)-acetamide are introduced, atambient temperature, into a 250 milliliters glass flask equipped with awater separator. 3.2 g (3.6×10⁻² mol) of freshly distilled pyruvic acidand 120 milliliters of benzene are then added. This mixture is thenheated to the reflux temperature; when refluxing starts, the solutionbecomes clear, and then clouds gradually due to the precipitation of thepara-(methoxyphenylacetyl)-dehydroalanine. Refluxing is continued untilwater no longer separates out, this requiring about 48 hours, afterwhich the benzene is stripped off in vacuo.

The para-(methoxyphenylacetyl)-dehydroalanine is extracted by means of asaturated NaHCO₃ solution, and 1.7 g of unreactedpara-(methoxyphenyl)-acetamide are then filtered off.

When the filtration is complete, a few milliliters of hydrochloric acidare added dropwise until a pH of about 3 or 4 is obtained. Thepara-(methoxyphenylacetyl)dehydroalanine precipitates and is recoveredby filtration and recrystallisation from ethanol. 4.45 g ofpara-(methoxyphenylacetyl)-dehydroalanine are obtained, in a yield of62%. The melting point of the product obtained is found to be 186° C.The infra-red spectrum (KBr) reveals absorption bands at 3400 cm⁻¹(--OH), 1700 cm⁻¹ (C═O), 1620 cm⁻¹ (C═C), 1510 cm⁻¹, 1420 cm⁻¹ and 1300cm⁻¹. Mass spectrography reveals a peak at 235.

The nuclear magnetic resonance spectrum ofpara(methoxyphenylacetyl)-dehydroalanine, dissolved in dimethylsulphoxide, shows the following chemical shifts, the values being givenin δ (ppm): 1H s 8.96; 2H m 7.20; 2H m 6.86; 1H s 6.32; 1H s 5.69; 3H s3.73; 2H s 3.61.

EXAMPLE 2 Pharmaceutical composition

A pharmaceutical composition is prepared by mixing 4 g ofpara-(methoxyphenylacetyl)-dehydroalanine obtained according to Example1 and 3.2 g of cyclophosphamide.

One million "Taper Liver Tumor" cancer cells are injectedintraperitoneally into a group of 10 mice each weighing about 30 g. 48hours after this injection, the pharmaceutical composition describedabove is administered again intraperitoneally, in an amount of 180 mgper kg of mouse.

By way of comparison, a group of 10 similar mice to which likewise onemillion "Taper Liver Tumor" cancer cells have been administered issubjected solely to administration of cyclophosphamide, byintraperitoneal injection, 48 hours after administration of the cancercells, and a group of 10 other similar mice, to which, again, onemillion "Taper Liver Tumor" cancer cells have been administered is notsubjected to any further treatment whatsoever.

Amongst the group of mice not subjected to any further treatmentwhatsoever, all die between the eighteenth and the twenty-third day.

Amongst the group of mice only treated with cyclophosphamide, all diebetween the twenty-second day and the twenty-fifth day.

Amongst the group of mice treated with the pharmaceutical compositionaccording to the invention the mice only die beteen the twenty-eighthand thirty-ninth day.

The treatment of the ascites with the pharmaceutical compositionaccording to the invention thus allows the life of the affected mice tobe extended substantially.

EXAMPLE 3 Pharmaceutical compositions containing cyclophosphamide andpara-(methoxyphenylacetyl)-dehydroalanine: variation of the amount ofpara-(methoxyphenylacetyl)dehydroalanine introduced

One million "Taper Liver Tumor" cancer cells are injectedintraperitoneally into groups of twelve adult male mice, NMRI strain,the mice having a body weight of about 30 grams. 48 hours after thisinjection various pharmaceutical compositions according to the inventionare administered, again intraperitoneally, to the mice, the amount ofpara-(methoxyphenylacetyl)-dehydroalanine present in the compositionadministered being varied, and compositions only containingcyclophosphamide also beino administered.

Thereafter, three parameters are measured:

(a) the variations of the mean weight of the mice on the fifth day afterinoculation of the cancer tumour (V.M.W.)

(b) the median survival of 12 mice treated with a pharmaceuticalcomposition according to the invention or treated with cyclophosphamidealone (M.S.)

(c) the prolongation of survival of the mice treated with a compositionaccording to the invention relative to comparison mice treated withcyclophosphamide alone (P.S.).

The results obtained are listed in the table below, thepara-(methoxyphenylacetyl)-dehydroalanine being referred to by the codeS 86. The results reveal a prolongation of survival of the mice if apharaceutical composition containing doses of 25, 50 or 100 mg/kg of S86 is administered; the lethal dose (LD₅₀) of S 86 is greater than 400mg per kg of bodyweight in the mouse, this value being the maximum whichcan be injected into the mouse because of the low solubility of theproduct.

                  TABLE I                                                         ______________________________________                                        Pharmaceutical composition   M.S.    P.S.                                     and dose administered                                                                            V.M.W.    (day)   (%)                                      ______________________________________                                        Cyclophosphamide                                                                           80 mg/kg  -1        24                                           Cyclophosphamide +                                                                         80 mg/kg  -7.8      18    -25                                    S 86         400 mg/kg                                                        Cyclophosphamide +                                                                         80 mg/kg  -5        24      0                                    S 86         200 mg/kg                                                        Cyclophosphamide +                                                                         80 mg/kg  -3        26    +15                                    S 86         100 mg/kg                                                        Cyclophosphamide +                                                                         80 mg/kg  -2        27.5  +15                                    S 86         50 mg/kg                                                         Cyclophosphamide +                                                                         80 mg/kg  -4        26     +9                                    S 86         25 mg/kg                                                         ______________________________________                                    

EXAMPLE 4 Pharmaceutical compositions containing cyclophosphamide andpara-(methoxyphenylacetyl)-dehydroalanine: variation of the amount ofcyclophosphamide introduced

One million "Taper Liver Tumor" cancer cells are injectedintraperitoneally into groups of twelve adult male mice, NMRI strain,the mice having a body weight of about 30 grams. 48 hours after thisinjection various pharmaceutical compositions according to the inventionare administered, again intraperitoneally, to the mice, the amount ofcyclophosphamide present in the composition administered being varied,and compositions only containing cyclophosphamide also beingadministered.

Thereafter, three parameters are measured:

(a) the variation of the mean weight of the mice on the fifth day afterinoculation of the cancer tumour (V.M.W.)

(b) the median survival of 12 mice treated with a pharmaceuticalcomposition according to the invention or treated with cyclophosphamidealone (M.S.)

(c) the prolongation of survival of the mice treated with a compositionaccording to the invention relative to comparison mice treated with thesame dose of cyclophosphamide (P.S).

The results obtained are listed in the table below, thepara-(methoxyphenylacetyl)-dehydroalanine being referred to by the codeS 86. They show a marked prolongation of the survival time whenpharmaceutical compositions according to the invention containing dosesof cyclophosphamide equal to or greater than 360 mg/kg are administered.It is also noticeable that the mean weight of the mice varies less inthe case of the mice treated with pharmaceutical compositions accordingto the invention than in the case of the mice treated withcyclophosphamide.

                  TABLE II                                                        ______________________________________                                        Pharmaceutical composition   M.S.    P.S.                                     and dose administered                                                                            V.M.W.    (day)   (%)                                      ______________________________________                                        Cyclophosphamide                                                                            80 mg/kg -2.2      21                                           Cyclophosphamide +                                                                          80 mg/kg -2.6      22     +5                                    S 86          50 mg/kg                                                        Cyclophosphamide                                                                           180 mg/kg -4.4      23                                           Cyclophosphamide +                                                                         180 mg/kg -3        18.5  -17                                    S 86          50 mg/kg                                                        Cyclophosphamide                                                                           360 mg/kg -6.6      31                                           Cyclophosphamide +                                                                         360 mg/kg -10       34    +10                                    S 86          50 mg/kg                                                        Cyclophosphamide                                                                           450 mg/kg -14       20                                           Cyclophosphamide +                                                                         450 mg/kg -10.4     34    +70                                    S 86          50 mg/kg                                                        Cyclophosphamide                                                                           540 mg/kg -18.6     12                                           Cyclophosphamide +                                                                         540 mg/kg -11.6     38.5  +204                                   S 86          50 mg/kg                                                        ______________________________________                                    

EXAMPLE 5 Inhibition of the toxicity of doxorubicin in vivo

Subcutaneous injection of a single dose of doxorubicin (10 mg/kg) torats causes, in the liver, a reduction of 20% in the minimum content ofcytochrome P450, a drop in benzo(a)pyrene hydroxylase activity and areduction of 85% in the aldrin mono-oxygenase activity. Theadministration of cysteamine, used as a reference antitoxic substance,does not protect against the effect of doxorubicin on the level ofcytochrome P450. On the other hand the drop in benzo(a)pyrenehydroxylase activity is no more than 20% and the decrease in aldrinmono-oxygenase activity is reduced to 40%.

A single dose (10 mg/kg) of a composition containing equal amounts byweight of doxorubicin and of para-(methoxyphenylacetyl)-dehydroalaninewas injected into rats. A 60% increase in the minimum content ofcytochrome P450, a 20% increase in the benzo(a)pyrene hydroxylaseactivity and a 5% decrease in the aldrin mono-oxygenase activity wereobserved.

It emerges from these tests that the acylated enamide compound accordingto the invention completely protects against the abovementioned threetoxic effects of doxorubicin.

EXAMPLE 6 Pharmaceutical composition

A pharmaceutical composition is prepared by mixing 4 g ofpara-(methoxyphenylacetyl)-dehydroalanine obtained according to Example1 and 0.2 g of doxorubicin.

One million L311 leukaemia cells are injected intraperitoneally into agroup of six rats, LOU/2 strain, the mean body weight of the rats being160 g. L311 leukaemia is a tumour transplantable in rats of strainLOU/2, the tumour being described in the article by C. Deckers, F. Mare,L. Deckers-Passeu and A. Trouet, Adriamycin Review, Part I, 1973, pages79 to 86.

48 hours after this injection the pharmaceutical composition describedabove is administered to the rats, again intraperitoneally, in an amountof 105 mg per kg of rat.

By way of comparison, a group of twelve similar rats to which onemillion L311 leukaemia cells have also been administered is subjectedsolely to intraperitoneal administration of doxorubicin 48 hours afterthe administration of the L311 leukaemia cells, and a group of twelvesimilar rats to which one million L311 leukaemia cells have also beenadministered is given no subsequent treatment whatsoever.

The mean length of survival after administration of the leukaemia cellsis 15.9 days in the case of the untreated leukaemic rats, 27.6 days forthose treated solely with doxorubicin and 33.6 days for the rats treatedwith the composition according to the invention.

For the untreated leukaemic rats, the first death occurs fourteen daysafter administration of the leukaemia cells. The corresponding figure issixteen days for the rats treated with doxorubicin and twenty-one daysfor the rats treated with the composition according to the invention.

The treatment of leukaemia with the compositions according to theinvention thus permits a substantial prolongation of life of theleukaemic rats.

EXAMPLES 7 TO 11

Following a method similar to that described in Example 1, the compoundsof the general formula (I) in which n=1 and Z has the meaning indicatedbelow were prepared.

    ______________________________________                                        Example                  Yield   Melting                                      No.      Z               (%)     point (°C.)                           ______________________________________                                        7        --OC.sub.2 H.sub.5                                                                            41      142                                          8        --OCH.sub.2 --C.sub.6 H.sub.5                                                                 62      188                                          9        --OCH.sub.2 --CH.sub.2 --CH.sub.3                                                             30      178                                          10       --OCH(CH.sub.3).sub.2                                                                         18      173                                          11       --SCH.sub.3     71      209                                          ______________________________________                                    

These compounds exhibit a detoxifying effect similar to that of thecompound of Example 1.

EXAMPLE 12 Preparation of sodiumα-(para-methoxyphenyl)acetamido-acrylate[sodiumN-(para-methoxyphenylacetyl)dehydroalaninate]

2.35 g (10⁻² mol) of the acid (para-methoxyphenylacetyl-dehydroalanine)are dissolved in 100 ml of methanol containing 0.54 g of sodiummethanolate.

Evaporation of the solvent gives a white solid.

Recrystallisation from isopropanol gives 2.25 g (87%) of the sodiumsalt.

Melting point: 112° C. (polymerisation).

NMR (D₂ O)δ (ppm): 7.0-6.5(4H, m) 5.7(1H, s) 5.4(1H, s) 4.5(H₂ O)3.5(3H, s) 3.3(2H, s).

We claim:
 1. Acylated enamide compounds, characterised in that they arecompounds corresponding to the general formula ##STR6## in which Zrepresents an electron donor group selected from the electron donorgroups comprising a halogen or a chemical group selected from the groupscomprising OR², SR², SeR², N═R² or NR² R³, in which the oxygen (O),sulphur (S), selenium (Se) and nitrogen (N) can form part of a ring andR² and R³ can be identical or different and represent hydrogen or asaturated or unsaturated aliphatic or cyclic organic group containing 1to 20 carbon atoms;n is 1, 2 or 3; and R¹ represents hydrogen, ahalogen, a substituted or unsubstituted aliphatic group containing from1 to 4 carbon atoms or an aromatic group containing from 5 to 8 carbonatoms; or salts, complexes, alkylated derivatives or acylatedderivatives of these compounds.
 2. Acylated compounds according to claim1 wherein Z is an OR² group, where R² represents hydrogen or asubstituted or unsubstituted alkyl group having from 1 to 6 carbonatoms.
 3. Acylated enamide compounds according to any one of claims 1,or 2 characterised in that they consist of(methoxyphenylacetyl)-dehydroalanines.
 4. Acylated enamide compoundsaccording to any one of claims 1, 2 or 3, used as a medicament. 5.Pharmaceutical compositions consisting essentially of an acylatedenamide compound according to any one of claims 1, 2 or 3 and apharmaceutically acceptable carrier.
 6. Pharmaceutical compositionsaccording to claim 5, including an antineoplastic substance selectedfrom the group comprising nitrogen mustard, an antibiotic oranti-pyrimidine compound.
 7. Pharmaceutical compositions according toclaim 6, wherein the antineoplastic substance is cyclophosphamide,daunorubicin, fluorouracil or doxorubicin.
 8. Pharmaceuticalcompositions according to claim 5 used in the treatment of liver andleukemia cancers.
 9. Process for the preparation of acylated enamidecompounds according to any one of claims 1, 2 or 3, characterised inthat an amide of the formula ##STR7## is reacted with pyruvic acidwherein: Z represents an electron donor group selected from the electrondonor groups comprising a halogen or a chemical group selected from thegroups comprising OR², SR², SeR², N═R² or NR² R³, in which the oxygen(O), sulphur (S), selenium (Se) and nitrogen (N) can form part of a ringand R² and R³ can be identical or different and represent hydrogen or asaturated or unsaturated aliphatic or cyclic organic group containing 1to 20 carbon atoms;n is 1, 2 or 3; and R¹ represents hydrogen, ahalogen, a substituted or unsubstituted aliphatic group containing from1 to 4 carbon atoms or an aromatic group containing from 5 to 8 carbonatoms; or salts, complexes, alkylated derivatives or acylatedderivatives of these compounds.
 10. Pharmaceutical compositionsaccording to claim 6 used in the treatment of liver and leukemiacancers.
 11. Pharmaceutical compositions according to claim 7 used inthe treatment of liver and leukemia cancers.